Growth inhibition of mammary epithelium by transforming growth factor-beta (TGF-beta) is a classic example of the strong antiproliferative action of this cytokine in epithelial cells. We have intensely studied TGF-beta signal transduction and its antiproliferative mechanisms, and have achieved a solid understanding of these processes and their implications in cancer. We have started to focus on the problem of TGF-beta and breast cancer. An important recent discovery is that TGF-beta may play a dual role in breast cancer. On one hand, the ability of TGF-beta to inhibit cell proliferation is diminished or lost in breast cancer cells. On the other, TGF-beta can exacerbate tumor progression by fostering invasion and metastasis. This is manifest in breast cancer cells that retain TGF-beta signaling components but have selectively lost the antimitogenic response, as is the case in cells harboring a hyperactive ErbB-2/Ras pathway. We have defined mechanisms of cell cycle arrest by TGF-beta in mammary epithelial cells, and how these mechanisms are inactivated downstream of TGF-beta receptors and Smad mediator proteins in breast cancer cells. Building on this knowledge, we propose to delineate the basis for TGF-beta stimulation of mammary tumor progression, and identify ways to inhibit this process. We will pursue five specific aims focusing on the role of TGF-beta in breast cancer progression and metastasis. By crossing MMTV-Erb2 or MMTV-Wnt1 transgenic mice to gain-of-function and loss-of-function TGF-beta receptor transgenic mice we will seek to generate models of TGF-beta action in breast cancer progression and metastasis. Based on our knowledge of the TGF-beta operating system, we will search for tumorigenic TGF-beta gene responses in breast cancer and the components that enable these responses. More broadly, we will also seek to identify genes that enable the bone metastasis activity of breast cancer cells. Finally, we will devise assays for the identification of inhibitors of TGF-beta tumorigenic effects. Our interactions with other members of the Program Project, either as recipients of their mouse strains and genetic manipulation techniques (Varmus, Benezra), as providers of genetically altered mouse strains for anti-tumor drug pre-clinical studies (Rosen), or as beneficiaries of tumor imaging technology (Imaging Core) should provide us with a singular opportunity to achieve progress in the understanding of cancer progression.